The effective diagnosis and treatment of cancer at an early stage in its development ordinarily improves the prospects for a successful clinical outcome. Unfortunately, ovarian cancer is notoriously difficult to detect in its early stages.
Over 85% of human ovarian carcinomas are thought to arise from the ovarian surface epithelium (OSE). OSE-derived carcinomas are the fifth or sixth most frequent malignancy in American women and the five year survival rate of patients with ovarian cancer is no better than 37%.
In recent years, the availability of several tumor markers has improved the diagnostic and prognostic accuracy in the management of ovarian carcinomas. Serous cystadenocarcinoma ovarian tumor associated antigen CA125 is currently the serum marker of choice for monitoring the progression of OSE carcinomas. Elevated serum levels of CA125 antigen are detectable in approximately 80-90% of ovarian cancer patients. The presence of CA125 is typically detected by radioimmunoassays employing monoclonal antibodies such as OC125 which bind specifically to the CA125 antigenic determinant.
Various United States patents have previously issued pertaining to the use of monoclonal antibodies to detect the presence of CA125 in sera. For example, U.S. Pat. No. 5,366,866, Xu et al., issued 22 Nov., 1994, relates to a method of diagnosing and monitoring the progression of ovarian and endometrial cancers using monoclonal antibodies reactive with CA125 present in sera, blood plasma or other biological fluids.
While measurement of serum CA125 levels is an effective tool for monitoring the progression of ovarian cancers, it is not reliable as a predictive marker for identifying healthy women at increased risk for ovarian cancer, or for detection of very early stages of the disease. Some women who are at an increased risk to develop ovarian cancer can be identified on the basis of family histories of ovarian, breast, or other related cancers and by genetic analysis. Numerous cytogenetic studies and loss of heterozygosity investigations have begun to suggest some genes or chromosomal regions involved in ovarian cancer initiation and progression (Pejovic et al., Genes Chromosomes Cancer, 1992; 4:58-68; Testa et al., Cancer Res., 1994; 54:2778-2784: Yang-Feng et al., Int. J. Cancer, 1993; 54:546-551). In situations where linkage analysis is feasible and linkage of affected family members can be shown through the only currently known locus, BRCA-1, family members predisposed to develop ovarian and/or breast cancer can be identified with good accuracy (Futreal et al., Science, 1994; 266:120-122). There are, however, individuals in families that may be linked through some yet to be identified locus or where linkage testing is not feasible. Such individuals could benefit from an alternative identification-of-risk strategy. Not all women in currently recognized risk categories will develop ovarian cancers, and additional contributing factors are poorly defined. The majority of ovarian cancers arise "sporadically" (i.e. in women without family histories).
One alternative strategy is to identify preneoplastic phenotypic changes in the OSE which could signal a predisposition to development of ovarian tumors. Unfortunately, little progress has been made thus far in the early detection of such preneoplastic tissue changes and no reliable tumor-associated tissue markers have yet been identified. This lack of information about early changes in the OSE poses a particular problem for women with hereditary ovarian cancer syndromes, where there is a need to define more reliable criteria for prevention and surveillance.
The need has therefore arisen for a new screening test for identifying and monitoring women at risk of developing OSE-derived carcinomas.